(+)-Bulbocapnine-â-N-oxide from Glaucium fimbrilligerum

Abbas Shafiee,* Katayoun Morteza-Semnani, and Mohsen Amini

Department of Chemistry, Faculty of Pharmacy, The Medical Sciences University of Tehran, Tehran, Iran

Received May 12, 1998

A new aporphine alkaloid, (+)-bulbocapnine-â-N-oxide (1), was isolated from Glaucium fimbrilligerum.Its structure and the stereochemistry at the N-oxide center were determined by spectroscopic methodsand confirmed by synthesis.

Seven plant families, viz. Annonaceae, Berberidaceae,Magnoliaceae, Menispermaceae, Monimiaceae, Papaver-aceae, and Ranunculaceae, are known to produce aporphineN-oxides.1 Since some enthusiasm for the clinical use ofN-oxides was engendered by their purported delayed-release properties, low toxicities, and low addictive proper-ties compared with the corresponding tertiary alkaloids,further study of these compounds may help to answer theintriguing question as to what alkaloids are doing inplants.2

In the course of a study of the chemical constituents ofthe Iranian flora, we had occasion to investigate thealkaloids of Glaucium fimbrilligerum Boiss., one of theIranian species belonging to the botanical family Papav-eraceae.3 The plant yielded the new aporphine (+)-bulb-ocapnine-â-N-oxide (1), C19H19NO5.

The 400 MHz 1H-NMR spectrum of 1 in CDCl3 exhibitedthe N-methyl signal at δ 3.45, while H-6a appeared as adoublet of doublets at δ 4.13. Difference NOE experimentswas used to settle the stereochemistry at the N-oxidecenter. Irradiation of the δ 3.45 N-methyl singlet led to a10.3% enhancement of the signal at δ 4.13 (H-6a). Con-versely, irradiation at δ 4.13 produced a 5.4% enhancementof the δ 3.45 singlet (N-CH3). It follows that the N-methylgroup and H-6a must be syn to each other. The (+)-bulbocapnine has the S configuration, therefore the (+)-bulbocapnine-â-N-oxide belongs to the C-6a S absoluteconfiguration as indicated in structure 1.4

The new alkaloid was identical in all respects with thesample of bulbocapnine-â-N-oxide prepared by treatmentof bulbocapnine with m-chloroperbenzoic acid.

Known alkaloids from the plant (1 kg) were bulbocapnine(4.7 g), protopine (3.9 g), isocorydine (2.4 g), N-methyllind-carpine (400 mg), salutaridine (100 mg), and thaliporphine

(30 mg). The alkaloids were identified by comparison withdata already reported (mp, IR, UV, 1H-NMR, and MS).5-7

Experimental Section

General Experimental Procedures. Melting points weretaken on a Kofler hot stage apparatus and are uncorrected.The UV spectra were recorded on a Perkin-Elmer 550 SEspectrophotometer. The IR spectra were obtained on a Perkin-Elmer 267 spectrophotometer. 1H- and 13C-NMR spectra wererecorded on a Bruker FT-80 or a Varian FT-400 unity plusspectrometer. Chemical shifts are reported in ppm from TMSas an internal standard and are given in δ units. The massspectra were run on a Finnigan TSQ-70 spectrometer at 70eV. Column chromatography was carried out on Si gel 60(230-400 mesh), column fractions were monitored via TLCover precoated sheets of Si gel 60 HF254+366 (0.2 mm layerthickness) under UV (254 and 366 nm), and the alkaloids weredetected by Dragendorff reagent.

Plant Material. G. fimbrilligerum Boiss. was collected inApril 1996 from Gaduk of Abbasabad, north of Iran andidentified by Dr. Gholamreza Amin, Department of Botany,Faculty of Pharmacy. A voucher specimen (no. 6507-T) isdeposited in the herbarium of this Faculty.

Extraction and Isolation. The aerial parts of plant (1kg) were extracted with methanol, and the solvent wasevaporated. To the residue was added 400 mL of acetic acidsolution (50%), and the mixure was filtered. The filtrate wasextracted with petroleum ether (4 × 150 mL) to remove thecolored material. The aqueous layer was made alkaline withammonia (25%) and extracted with CHCl3 (4 × 300 mL). TheCHCl3 extracts were pooled, dried (anhydrous Na2SO4), andfiltered. The filtrate was evaporated to give a crude mixtureof alkaloids (15 g). This residue was chromatographed overSi gel (500 g) in CHCl3, and elution was achieved via CHCl3

and CHCl3-MeOH mixtures of increasing polarity. Combinedfractions which were eluted with CHCl3-MeOH (90:10) hadone alkaloid which was crystallized from Me2CO to givebulbocapnine-â-N-oxide (1) (72 mg).

Bulbocapnine-â-N-oxide (1): white needles, mp 153-155°C; [R]20

D +180° (c 0.65, MeOH); UV (MeOH) λmax (log ε) 225(4.19), 269 (3.86), 307 (3.57) nm; IR (KBr) νmax 3380, 1050, 950cm-1; 1H-NMR (CDCl3, 400 MHz) δ 6.88, 6.84 (each 1H, d, J) 8 Hz, H-9, H-8), 6.69 (1H, s, H-3), 6.14, 5.94 (each 1H, d, J) 1.2 Hz, OCH2O), 4.13 (1H, dd, J ) 2.8, 2.8 Hz, H-6a), 3.90(3H, s, OCH3), 3.45 (3H, s, NCH3); 13C-NMR (CDCl3, 100.6MHz) δ 148.1 (s, C-10), 147.2 (s, C-2), 142.7 (s, C-11), 141.7 (s,C-1), 126.9 (s, C-7a), 124.6 (s, C-3a), 122.1 (s, C-1b), 119.4 (d,C-8), 117.2 (s, C-11a), 114.3 (s, C-1a), 110.9 (d, C-9), 107.2 (d,C-3), 100.6 (t, OCH2O), 71.4 (d, C-6a), 63.8 (t, C-5), 57.5 (q,NCH3), 56.1 (q, OCH3), 30.4 (t, C-7), 24.5 (t, C-4); EIMS m/z341 [M]+ (73), 325 (100), 310 (50), 295 (18), 282 (81), 165 (22),152 (21).

Preparation of 1. (+)-Bulbocapnine (200 mg) was dis-solved in CHCl3 (5 mL), and m-chloroperbenzoic acid (200 mg)

* To whom correspondence should be addressed. Tel.: +98 (021) 6406757.Fax: +98 (021) 6461178.

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in CHCl3 (5 mL) was added slowly. The ice-cold mixture wasstirred for 1 h, brought to room temperature, diluted withCHCl3, and washed with 10% aqueous NaHCO3 to removeexcess acid. The CHCl3 solution was washed with a little H2O,dried, filtered, and concentrated under vacuum to yield anamorphous solid, 199 mg (95%). Bulbocapnine-â-N-oxide wasseparated by TLC (solvent system: CCl4-n-BuOH-MeOH-conc. NH4OH, 40:30:30:10) to yield 160 mg (76%). It wasidentical with plant material (1) in terms of MS, 13C- and 1H-NMR spectra, TLC Rf value, mp, and specific rotation.

Acknowledgment. This work was partially supported bya grant from the research council of Tehran University ofMedical Sciences and IOCD.

References and Notes(1) Velcheva, M.P.; Petrova, R.R.; Samdanghiin, Z.; Danghaaghiin, S.;

Yansanghiin, Z.; Budzikiewicz, H.; Hesse, M. Phytochemistry 1996,42, 535-537.

(2) Evans, W.C. Trease and Evans’ Pharmacognosy; Alden Press: Oxford,1989; pp 544-545.

(3) Shafiee, A.; Ghanbarpour, A.; Akhlaghi, S. J. Nat. Prod. 1985, 48,855-856.

(4) Montgomery, C.T.; Freyer, A.J.; Guinaudeau, H.; Shamma, M.;Fagbule, M.O.; Olatunji, G.; Gbile, Z. J. Nat. Prod. 1985, 48, 833-834.

(5) Guinaudeau, H.; Leboeuf, M.; Cave, A. Lloydia 1975, 38, 275-338.(6) Guinaudeau, H.; Shamma, M. J. Nat. Prod. 1982, 45, 237-246.(7) Lalezari, I.; Shafiee, A.; Mahjour, M. J. Pharm. Sci. 1976, 65,

923-924.

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